Oncolytic viruses are designed to infect and destroy cancer cells, while leaving normal cells relatively unaffected (MacLean et al., J. Gen. Virol. 72:630-639 (1991); Robertson et al., J. Gen. Virol. 73:967-970 (1992); Brown et al., J. Gen. Virol. 75:3767-3686 (1994); Chou et al., Science 250:1262-1265 (1990)). One virus that has been of particular interest as an oncolytic is Herpes simplex virus-1 (HSV). HSV can infect a broad range of cell types and has large genome, which allows multiple therapeutic genes to be packaged into recombinants. Experimental evidence for the antitumor effect of HSV against gliomas has existed for over a decade (Martuza, et al., Science 252:854-856 (1991); see also: Mineta et al., Nature Med. 1:938-943 (1995); Market et al., J. Neurosurg. 77:590-594 (1992); Randazzo et al., Virology 211:94-101 (1995); Kesari et al., Lab. Invest. 73:636-648 (1995)) and more recent studies suggest that it should be effective for the treatment of tumors of the lung, liver and ovary as well (U.S. Pat. No. 6,428,968; see also Montgomery et al., Cell 87:427-436 (1996)). Unfortunately, attempts to develop viruses that only target or replicate in cancer cells while maintaining their cytolytic effectiveness has met with only limited success. For example, it has been found that the deletion of genes that impair viral replication in normal cells also leads to a significant decrease in the oncolytic activity of the virus in targeted tumor cells (Kramm, et al. Hum. Gene Ther. 8(17):2057-68 (1997); Advani, et al., Gene Ther 5(2):160-165 (1998); Chung, et al., J. Virol. 73(9):7556-64 (1999)).
Thus, it remains a great challenge to construct an oncolytic HSV recombinant that offers a high degree of safety while its replication capability in tumor cells remains at levels close to that of a wild-type virus. In principle, this can be achieved if one can construct an oncolytic recombinant virus whose de novo replication can be tightly controlled and adjusted by a pharmacological agent in the localized tumor microenvironment. This virus should minimize concerns regarding the potential unwanted spread of oncolytic virus to other tissues, prevent overloads of progeny oncolytic viruses at the end of tumor killing and quickly shut down the oncolytic activity of the virus if unwanted adverse effects are detected in a patient.
Recently, a tetracycline-inducible transcription switch for use in mammalian cells was developed (U.S. Pat. No. 6,444,871; Yao, et al., Hum. Gene Ther. 9:1939-1950 (1998)) and used to adapt HSV as a vector for delivering therapeutic genes to cells (US published application 2005-0266564). However, it has not been clear whether this degree of regulation is sufficient in controlling de novo replication of an oncolytic virus or whether it is possible to develop a safe and effective therapy that does not rely on viruses being highly specific for cancer cells.